Method of relieving pain employing 1, 3, 5-trihydroxy-benzene



United States Patent M 3,093,544 METHOD OF RELIEVING PAIN EMPLOYING1,3,5-TRIHYDROXY-BENZENE Louis Lafon, 86 Ave. de la Republique, Paris,France No Drawing. Filed Dec. 22, 1961, Ser. No. 161,397 Claimspriority, application Great Britain Dec. 30, 1959 7 Claims. (Cl.167--65) Phloroglucinol (1,3,5-trihydroxy-benzene) is a'solid in theform of rhombohedric prisms, the crystals of which include two moleculesof water of crystallisation. 'Ihe hydrated material melts at 117 C. and,if anhydrous, it melts around 218 C. under rapid heating and between 200and 209 C. under gentle heating; this substance is soluble in water andslightly soluble in alcohol and ether.

The applicant has discovered that phloroglucinol has very interestingantispasmodic properties, and pain relieving properties in themanagement of nephritic and hepatic colics.

Numerous pharmacological tests have been carried out in order to verifythat phloroglucinol can be used safely and with high activity intherapeutics.

In the first place, acute toxicity tests have been carried out. Acutetoxicity has been determined intraperitoneally on white mice. 44 femalemice of the Webster strain have been tested, having a Weight between 16and 25 g. Toxicity has been studied for dosages from 0.25 to 2 g. perkg; even at this latter dosage, no immediate mortality has-beenobserved. However, two mice out of twelve died after 23 hours.

Even at this dosage of 2 g. per kg., no respiratory, cardiac orconvulsive toxic phenomenon was noted after the injection. Merely acertain transient stimulation of the animal with running movements wasobserved.

In all cases, an abdominal contraction syndrome with elongation of thehindquarters was noted, which phenomenon persisted for 5 to mins.

Intravenous toxicity tests have also been carried out on dogsanaesthetised with chloral, by injecting doses varying from 25 to 250mg. per kg.; even at this latter dosage, which was injected into 8 dogs,no mortality was observed.

Study of the chronic toxicity of phloroglucinol has shown that, in dosesmarkedly greater than active doses, the product is entirely without anyrisk; the growth of rats absorbing the product mixed in concentrationsof OAS-0.62% with their food was not reduced in comparison with controlrats. Hematological examination allowed no anomalies to be observed.Examination of the vital organs and the weights showed no detectabledifference in comparison with the controls; in particular, there was noantithyroid action at these doses.

Females were mated with males; the fertility and fecundity of animals towhich phloroglucinol was administered were not substantially diiferentfrom those of control animals.

First generation animals had absorbed the product during 200 days andthose of the second generation during 60 days; no toxic or subtoxicphenomena were observed.

The antispasmodic efiect of phloroglucinol was then studied. For this,in a first series of experiments, female rats having a weight rangingbetween 75 and 200 g. were used, which were previously unfed for 20hours. The duodena of these rats were taken and maintained alive in astandard Tyrode solution prepared by means of double distilled wateroxygenated by aeration; the organs being maintained at a constanttemperature of +32 C.

29 rats were used in these experiments and each test was made on twoorgans or these animals.

Phloroglucinol was used in 1% solution and in 5% saturated solution andadded to Tyrode liquid so as to have a total volume of ccs. in each testtube.

For the dosage, the peristaltic movements were recorded when, after 15to 20 minutes immersion in the Tyrode solution, the duodenum was relaxedand about 10 mg. of barium chloride had been introduced into the bath.The preparation was washed, immediately after observing a musclecontraction and a state of persistent spasm, by means of a Tyrodesolution. After 15 mins., the experiment was repeated; if an identicalresponse was obtained, the preparation was washed immediately. The samequantity of barium chloride was then added to the Tyrode liquidcontaining the duodenum and, without effecting washing, 0.05 g., 0.10 g.and 0.15 g. of phloroglucinol per 80 ccs. was added.

In each case, an antispasmodic effect was obtained which was the greateras the dose of phloroglucinol was larger. The effect increased with theconcentration.

0n aver-age, the dose of 50 mg. for 80 ccs. of Tyrode exerted anantispasmodic action of 42%, the mg. dose an action of 70% and the ml.dose an action of 81%.

It was thus shown that phloroglucinol exerts a preventive effect on thespasmogenic action of barium chloride on isolated rat duodena.

Phloroglucinol has the property of alleviating the spasm of muscularorigin produced by barium chloride on the duodenum of the rat. Theefiiect of phloroglucinol isreversible by washing, also. After producinga moderate spasm by means of barium chloride and then alleviating thespasm with phloroglucinol, the muscle can be restored to its initialcondition by repeated washing and prolonged rest.

The antispasmodic effect of phloroglucinol has also been studied on theduodenum and ileum of the dog in situ. This action was studied on theintestinal spasm produced by barium chloride in the dog subjected toartificial respiration; the experiment was made on dogs anaesthetisedwith chloralose.

In all cases, 200 mg. of phloroglucinol per kg, injected intravenously,were suflicient to alleviate the spasm produced by 3 mg. of bariumchloride per kg. Slowing of the peristaltic contractions was alsoobserved.

Study of the antispasmodic action of phloroglucinol has also been madeon isolated dog and guinea-pig ureters. It has been established that, onthese isolated organs, phloroglucinol does not modify the effect ofacetylcholine, although it is alleviated by atropine; phloroglucinolalleviates the spasm produced by barium chloride and is capable ofpreventing the spasmogenic effect of barium chloride on the isolatedureter.

This product thus exerts on the isolated ureter an efiect analogous tothat observed on a smooth muscle such as an isolated rat duodenum.

An attempt was also made to establish the pharmacodynarnic spectrum ofphloroglucinol.

The cardiovascular effect was studied upon dogs normotensivelyanesthetised with chloral.

The carotid pressure of several dogs was recorded and it was observedthat injection of 25 to 75 mg. per kg. of phloroglucinol caused nochange in this pressure.

On the contrary, with all the animals, injection of 200 to 250 mg. perkg. of phloroglucinol caused a diminution in the carotid pressure whichvaried according to the animals from 20 to 60%.

The coronary vasodilator effect was studied by the classical techniqueof Langendorff, on isolated rabbit heart. For this purpose, an isolatedrabbit heart was sufiused using an oxygenated Van Dyke Hastingssolution. After having established the output of sulfusion of the base,a dilute solution of phloroglucinol was in- Pat'ented June 11, 1963jected into the tube connecting the sutfusing device to the nozzle. Thisexperiment was carried out on several rabbits; doses from 0.1 to 10 mg.of phloroglncinol were without effect. Doses of 50 to 100 mg. ofphloroglucinol caused vasodilation ranging between 10 and 200%.

'Clinitical tests have also been carried out, at the H6 pital Bichat inParis, patients being given cachets cntaining phloroglucinol indifferent doses and cachets solely containing glucose.

With twenty patients, it was observed that phloroglucinol, employed inthe form of cachets containing one part of phloroglucinol to nine partsof glucose, had a certain efiicacy as an antispasmodic and weretolerated perfectly.

On another twenty patients suffering from hepatitis, phloroglucinolinhibited, in almost every case, the pain caused by the influence ofsodium dehydrocholate and morphine hydrochloride.

1 to 3 cachets per day containing 10 mg. of phloroglucinol and 90 mg. ofglucose, in the case of calcified cholecystitis and hepatitis,diminished and often even eliminated the depression.

On the other hand, twelve patients had their nephritic crises calmed bythe administration, during the period of depression, of two cachetscontaining 5 mg. of phloroglucinol.

It was observed that phloroglucinol exerted a certain effect in eachcase, even in a dose of mg, use in the form of cachets, capsules,powders or tablets giving equally good results.

Other clinical tests carried out at the Hopital Saint Louis in Parishave shown that phloroglucinol has a spectacular action in the treatmentof nephritic colic, the product being associated with a reducing sugarsuch as glucose, fructose or levulose in doses of 5 to 40 mg. per unit(cachet or tablet).

The present invention accordingly consists in a pharmaceuticalcomposition suitable for use as an antispasmodic, which comprisesphloroglucinol and one or more inert or active substances in admixturetherewith. The

other substance or substances may be solid or liquid,

such as a solvent, dispersant or other carrier for the phloroglucinoland the composition may be made in the form of a cachet, capsule orother dosage unit as described above.

This application is a continuation-in-part of my application Serial No.75,682, filed December 14, 1960, and now abandoned.

1 claim:

1. The method of relieving pain in the management of hepatic andnephritic colic which comprises administering to patients suffering suchcolic an amount of phloroglucinol sulficient to combat the colic.

2. The method of claim 1 in which the phloroglucinol is administered ina daily amount of 1 to 50 milligrams.

3. The method of claim 1 in which the phloroglucinol is administered ina daily amount of l to 50 milligrams combined with a reducing sugar inan amount ranging from 5 to milligrams per unit dose.

4. The method of claim 1 in which the phloroglucinol is administered ina daily amount of 1 to milligrams combined with a reducing sugarselected from the group consisting of glucose, fructose and levulose inan amount ranging from 5 to 40 milligrams per unit dose.

5. The method of claim 1 in which the phloroglucinol is administered ina daily amount of 1 to 50 milligrams combined with a reducing sugarselected from the group consisting of glucose, fructose and levulose inan amount ranging from 5 to 40 milligrams per unit dose, together with acarrier for said phloroglucinol.

6. The method of claim 5 in which the carrier is a phloroglucinolsolvent.

7. The method of claim 5 in which the carrier is a dispersant for thephloroglucinol.

References Cited in the tile of this patent Oettingen: Phenol and ItsDerivatives, National Institutes of Health Bulletin No. 190, US.Government Printing Oifice, Washington, DC, 1949, pp. l87188.

1. THE METHOD OF RELIEVING PAIN IN THE MANAGEMENT OF HEPATIC ANDNEPHRITIC COLIC WHICH COMPRISES ADMINISTERING TO PATIENTS SUFFERING SUCHCOLIC AN AMOUNT OF PHLOROGLOCINOL SUFFICIENT TO COMBAT THE COLIC.